JP3157117B2 - Optical resolution method of piperidine derivative - Google Patents
Optical resolution method of piperidine derivativeInfo
- Publication number
- JP3157117B2 JP3157117B2 JP34785196A JP34785196A JP3157117B2 JP 3157117 B2 JP3157117 B2 JP 3157117B2 JP 34785196 A JP34785196 A JP 34785196A JP 34785196 A JP34785196 A JP 34785196A JP 3157117 B2 JP3157117 B2 JP 3157117B2
- Authority
- JP
- Japan
- Prior art keywords
- propionic acid
- hydroxy
- methoxyphenyl
- piperidine
- salt
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
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- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
【０００１】[0001]
【発明の属する技術分野】本発明は、抗ヒスタミン活性
及び抗アレルギー活性を有する後記式（IV）のピペリジ
ン誘導体の光学活性体を製造する際、中間体として重要
な、４−〔（４−ハロゲノフェニル）（２−ピリジル）
メトキシ〕ピペリジンの光学分割方法に関する。TECHNICAL FIELD The present invention relates to an optically active isomer of a piperidine derivative of the formula (IV) having antihistamine activity and antiallergic activity, which is important as an intermediate, 4-[(4-halogeno). Phenyl) (2-pyridyl)
[Methoxy] piperidine.
【０００２】[0002]
【従来の技術】式（IV）2. Description of the Related Art Equation (IV)
【０００３】[0003]
【化７】 Embedded image
【０００４】（式中、Ｘはハロゲン原子を示し、Ａは炭
素数２−６のアルキレン基又はアルケニレン基を表し、
Ｂはヒドロキシル基等を表す）のピペリジン誘導体は、
次の反応式に示す方法により製造されることが知られて
いる（特公平５−３３９５３号公報）。(Wherein X represents a halogen atom, A represents an alkylene group or alkenylene group having 2 to 6 carbon atoms,
B represents a hydroxyl group, etc.)
It is known that it is produced by the method shown in the following reaction formula (Japanese Patent Publication No. 5-33953).
【０００５】[0005]
【化８】 Embedded image
【０００６】（式中、Ｘ、Ａ及びＢは前記と同一意味を
有し、Ｗは脱離基を表す）Wherein X, A and B have the same meaning as described above, and W represents a leaving group.
【０００７】このピペリジン誘導体を医薬としてより好
ましい光学活性体として効率よく製造するためには、中
間体を光学分割しこれを原料として用いることが望まし
いが、これまでその有効な方法は知られていない。In order to efficiently produce this piperidine derivative as a more preferable optically active substance as a medicine, it is desirable to optically resolve the intermediate and use it as a raw material, but no effective method has been known so far. .
【０００８】[0008]
【発明が解決しようとする課題及び解決手段】本発明者
らは、前記式（IV）のピペリジン誘導体を光学活性体と
して効率よく得るため、中間体である式（II）DISCLOSURE OF THE INVENTION The present inventors have found that the piperidine derivative of the formula (IV) can be efficiently obtained as an optically active substance, so that the intermediate of the formula (II)
【０００９】[0009]
【化９】 Embedded image
【００１０】（式中、Ｘはハロゲン原子を表す）で示さ
れるラセミ型ピペリジン誘導体をあらかじめ光学分割す
る方法につき鋭意研究を重ねた結果、光学分割剤として
式（III)As a result of intensive studies on the method of optically resolving the racemic piperidine derivative represented by the formula (wherein X represents a halogen atom), as a result of formula (III)
【００１１】[0011]
【化１０】 Embedded image
【００１２】（式中、Ｙは水素原子又はハロゲン原子を
表し、Ｚは低級アルコキシ基を表し、＊は不斉炭素を表
す）で示される光学活性プロピオン酸化合物を用いれば
効率よく光学分割できることを見出し、本発明を完成す
るに至った。(Wherein Y represents a hydrogen atom or a halogen atom, Z represents a lower alkoxy group, and * represents an asymmetric carbon). As a result, the present invention has been completed.
【００１３】即ち、本発明は、式（II）で示されるラセ
ミ型ピペリジン誘導体に、式（III)で示される光学活性
プロピオン酸化合物を作用させ、生成する２種のジアス
テレオマー塩の溶解度差を利用して、一方のジアステレ
オマー塩を分離・採取することを特徴とする式（II）の
ラセミ型ピペリジン誘導体の光学分割方法である。That is, the present invention relates to a method of reacting a racemic piperidine derivative represented by the formula (II) with an optically active propionic acid compound represented by the formula (III) to produce a difference in solubility between two diastereomeric salts formed. The method for optical resolution of a racemic piperidine derivative of the formula (II) is characterized in that one diastereomer salt is separated and collected by utilizing the following formula.
【００１４】本発明は、また、式（II）のラセミ型ピペ
リジン誘導体に、式（III)で示される光学活性プロピオ
ン酸化合物を作用させ、生成する２種のジアステレオマ
ー塩の溶解度差を利用して、一方のジアステレオマー塩
を分離・採取し、該塩を分解することを特徴とする、式
（Ｖ）The present invention also utilizes the difference in solubility between the two diastereomeric salts formed by reacting the racemic piperidine derivative of the formula (II) with the optically active propionic acid compound of the formula (III). Wherein one diastereomer salt is separated and collected, and the salt is decomposed.
【００１５】[0015]
【化１１】 Embedded image
【００１６】（式中、Ｘ及び＊は、前記と同一意味を有
する）で示される光学活性ピペリジン誘導体の製法であ
る。(Wherein, X and * have the same meanings as described above).
【００１７】本発明は、更に、式（Ｉ）The present invention further provides a compound of the formula
【００１８】[0018]
【化１２】 Embedded image
【００１９】（式中、＊、Ｘ、Ｙ及びＺは前記と同一意
味を有する）で示される光学活性ピペリジン誘導体と光
学活性プロピオン酸化合物との塩である。(Wherein *, X, Y and Z have the same meanings as described above), which is a salt of an optically active piperidine derivative and an optically active propionic acid compound.
【００２０】[0020]
【発明の実施の形態】本発明の方法は、適当な溶媒に式
（II）のラセミ型ピペリジン誘導体と式（III)の光学活
性プロピオン酸化合物を溶解し、生成する難溶性ジアス
テレオマー塩を析出させ、これを分離・採取することに
より実施できる。BEST MODE FOR CARRYING OUT THE INVENTION The process of the present invention comprises the steps of dissolving a racemic piperidine derivative of the formula (II) and an optically active propionic acid compound of the formula (III) in an appropriate solvent, and forming a poorly soluble diastereomer salt. It can be carried out by precipitating, separating and collecting.
【００２１】光学活性プロピオン化合物の具体例として
は、式（III)において、Ｙが水素原子又は塩素原子であ
り、Ｚがメトキシ基である化合物が挙げられる。これら
のうち好ましい例として、（２Ｒ，３Ｒ）−２−ヒドロ
キシ−３−（４−メトキシフェニル）−３−（２−ニト
ロ−５−クロロフェニルチオ）プロピオン酸、（２Ｒ，
３Ｒ）−２−ヒドロキシ−３−（４−メトキシフェニ
ル）−３−（２−ニトロフェニルチオ）プロピオン酸、
（２Ｓ，３Ｓ）−２−ヒドロキシ−３−（４−メトキシ
フェニル）−３−（２−ニトロ−５−クロロフェニルチ
オ）プロピオン酸及び（２Ｓ，３Ｓ）−２−ヒドロキシ
−３−（４−メトキシフェニル）−３−（２−ニトロフ
ェニルチオ）プロピオン酸を挙げることができ、これら
のうちとりわけ（２Ｒ，３Ｒ）−２−ヒドロキシ−３−
（４−メトキシフェニル）−３−（２−ニトロ−５−ク
ロロフェニルチオ）プロピオン酸が好ましい。ここで、
式（III)の光学活性プロピオン酸化合物が（２Ｒ，３
Ｒ）−体である場合は、式（Ｖ）の光学活性ピペリジン
誘導体のうちの（Ｓ）型異性体との塩が難溶性の塩とし
て析出し、式（III)の光学活性プロピオン酸誘導体が
（２Ｓ，３Ｓ）−体である場合は、式（Ｖ）の光学活性
ピペリジン誘導体のうちの（Ｒ）型異性体との塩が難溶
性の塩として析出する。Specific examples of the optically active propion compound include compounds in which Y is a hydrogen atom or a chlorine atom and Z is a methoxy group in the formula (III). Among these, preferred examples are (2R, 3R) -2-hydroxy-3- (4-methoxyphenyl) -3- (2-nitro-5-chlorophenylthio) propionic acid, (2R, 3R)
3R) -2-hydroxy-3- (4-methoxyphenyl) -3- (2-nitrophenylthio) propionic acid,
(2S, 3S) -2-hydroxy-3- (4-methoxyphenyl) -3- (2-nitro-5-chlorophenylthio) propionic acid and (2S, 3S) -2-hydroxy-3- (4-methoxy Phenyl) -3- (2-nitrophenylthio) propionic acid, among which (2R, 3R) -2-hydroxy-3-
(4-Methoxyphenyl) -3- (2-nitro-5-chlorophenylthio) propionic acid is preferred. here,
The optically active propionic acid compound of the formula (III) is (2R, 3
In the case of the R) -form, the salt with the (S) type isomer of the optically active piperidine derivative of the formula (V) precipitates as a poorly soluble salt, and the optically active propionic acid derivative of the formula (III) is In the case of the (2S, 3S) -isomer, a salt with the (R) isomer of the optically active piperidine derivative of the formula (V) precipitates as a hardly soluble salt.
【００２２】光学分割剤として用いられる式（III)の光
学活性プロピオン酸化合物の使用量は、特に限定される
ものではないが、式（II）のラセミ型ピペリジン化合物
１モルに対して０．５〜１．５倍モル、好ましくは０．
６〜１．１倍モルを使用するのが好ましい。The amount of the optically active propionic acid compound of the formula (III) used as the optical resolving agent is not particularly limited, but may be 0.5 to 1 mol of the racemic piperidine compound of the formula (II). ~ 1.5 times mol, preferably 0.1 mol.
It is preferable to use 6 to 1.1 times mol.
【００２３】本発明において原料として用いる式（II）
のラセミ型ピペリジン誘導体は、（Ｓ）型異性体及び
（Ｒ）型異性体の等量混合物で十分であるが、異性体の
混合比は、必ずしも等量でなくともよく、いずれか一方
が多く含まれた混合物であってもよい。Formula (II) used as a raw material in the present invention
In the racemic piperidine derivative of (1), an equivalent mixture of the (S) isomer and the (R) isomer is sufficient, but the mixing ratio of the isomers does not necessarily have to be equal, and one of the isomers is often used. It may be a contained mixture.
【００２４】式（II) のラセミ型ピペリジン誘導体は、
塩酸塩のような酸付加塩を用いることもでき、その場合
は、例えば反応系に水酸化アルカリ（例えば、水酸化ナ
トリウム）のような塩基を加えれば塩交換がおこり、遊
離のピペリジン化合物となる。また式（III)のプロピオ
ン酸化合物の光学活性体としては塩基との塩を用いるこ
ともでき、その場合は、反応系に塩酸のような酸を加え
れば遊離のプロピオン酸化合物となる。The racemic piperidine derivative of the formula (II)
An acid addition salt such as a hydrochloride can also be used. In this case, for example, when a base such as an alkali hydroxide (for example, sodium hydroxide) is added to the reaction system, salt exchange occurs and a free piperidine compound is obtained. . A salt with a base can also be used as an optically active form of the propionic acid compound of the formula (III). In this case, a free propionic acid compound can be obtained by adding an acid such as hydrochloric acid to the reaction system.
【００２５】本発明の方法で用いられる溶媒としては、
メタノール、エタノール、プロパノールのようなアルコ
ール類；アセトン、メチルエチルケトンのようなケトン
類；酢酸メチル、酢酸エチルのようなカルボン酸のエス
テル類；アセトニトリル、プロピオニトリルのようなニ
トリル類；ジオキサン、テトラヒドロフランのようなエ
ーテル類；ジメチルホルムアミドのようなアミド類又は
水等が挙げられ、とりわけアルコール類、水が好まし
い。これらの溶媒は、単独で用いてもよいが、必要に応
じて適当な比率で２種類又はそれ以上を混合して用いて
もよく、とりわけ、アルコール類と水との混合溶媒が好
ましい。溶媒の使用量は特に制限はないが、ラセミ型ピ
ペリジン誘導体に対し、例えば５〜５０重量部を用いれ
ばよい。The solvent used in the method of the present invention includes:
Alcohols such as methanol, ethanol and propanol; ketones such as acetone and methyl ethyl ketone; esters of carboxylic acids such as methyl acetate and ethyl acetate; nitriles such as acetonitrile and propionitrile; dioxane and tetrahydrofuran Ethers; amides such as dimethylformamide or water; and alcohols and water are particularly preferable. These solvents may be used alone, or may be used in combination of two or more at an appropriate ratio, if necessary, and a mixed solvent of alcohols and water is particularly preferable. The amount of the solvent used is not particularly limited, but may be, for example, 5 to 50 parts by weight based on the racemic piperidine derivative.
【００２６】本発明の方法において、生成する２種のジ
アステレオマー塩の溶解度の差は十分大きいため、特別
な結晶化の操作をせずとも難溶性ジアステレオマー塩
が、静置又は攪拌下で反応液から容易に析出してくる。In the method of the present invention, since the difference in solubility between the two diastereomeric salts formed is sufficiently large, the sparingly soluble diastereomeric salts can be left standing or stirred without special crystallization operation. Easily precipitates from the reaction solution.
【００２７】式（II）のラセミ型ピペリジン誘導体と式
（III)の光学活性プロピオン酸化合物の溶媒への溶解及
び続く難溶性ジアステレオマー塩の析出の際の条件には
特に制限はないが、例えば、両化合物の溶媒への溶解は
加温〜加熱下に実施でき、続く難溶性ジアステレオマー
塩の析出は冷却〜加温下に実施することができる。The conditions for dissolving the racemic piperidine derivative of the formula (II) and the optically active propionic acid compound of the formula (III) in a solvent and the subsequent precipitation of a sparingly soluble diastereomer salt are not particularly limited. For example, both compounds can be dissolved in a solvent under heating to heating, and the subsequent precipitation of a sparingly soluble diastereomer salt can be performed under cooling to heating.
【００２８】反応液から難溶性ジアステレオマー塩を析
出させるのに通常は種結晶を接種する必要はないが、析
出をより容易にするため目的とするジアステレオマー塩
と同種の結晶を接種してもよい。Usually, it is not necessary to inoculate a seed crystal to precipitate a sparingly soluble diastereomer salt from the reaction solution. However, in order to make the precipitation easier, the seed is inoculated with a crystal of the same species as the intended diastereomer salt. You may.
【００２９】また、難溶性ジアステレオマー塩を分離し
た後の母液を濃縮し、難溶性ジアステレオマー塩として
析出しなかった方のジアステレオマー塩を分離・採取
し、次いで該塩を分解するか、又は、難溶性ジアステレ
オマー塩を分離した後の母液を適当な有機溶媒で抽出
し、鏡像体である光学活性ピペリジン誘導体を回収して
もよい。Further, the mother liquor after separating the hardly soluble diastereomer salt is concentrated, and the diastereomer salt which has not been precipitated as the hardly soluble diastereomer salt is separated and collected, and then the salt is decomposed. Alternatively, the mother liquor after separation of the poorly soluble diastereomer salt may be extracted with an appropriate organic solvent to recover the optically active piperidine derivative as an enantiomer.
【００３０】また分離・採取したジアステレオマー塩
は、必要に応じて再結晶することにより更に純度を高め
ることができる。The purity of the separated and collected diastereomer salt can be further increased by recrystallization as needed.
【００３１】かくして採取されたジアステレオマー塩
は、公知の塩分解の方法により塩を脱離し、目的とする
光学活性ピペリジン誘導体を得ることができる。例え
ば、適当な溶媒（例えば、水−ジメチルホルムアミドの
混合溶液など）に溶解し、適当なアルカリ（例えば、水
酸化ナトリウム、水酸化カリウムなど）で処理して、こ
れを適当な抽出溶媒（例えば、エーテル、酢酸エチル、
クロロホルム、塩化メチレン、トルエンなど）で抽出
後、抽出溶媒を留去することにより、光学活性ピペリジ
ン誘導体を得ることができる。The diastereomer salt thus collected is eliminated from the salt by a known salt-decomposing method to obtain the desired optically active piperidine derivative. For example, it is dissolved in a suitable solvent (for example, a mixed solution of water-dimethylformamide and the like), treated with a suitable alkali (for example, sodium hydroxide, potassium hydroxide and the like), and then dissolved in a suitable extraction solvent (for example, Ether, ethyl acetate,
After extraction with chloroform, methylene chloride, toluene, etc.), the extraction solvent is distilled off to obtain an optically active piperidine derivative.
【００３２】また、抽出後の水層を適当な鉱酸（例え
ば、塩酸、硫酸など）で処理後、適当な溶媒（例えば、
エーテル、酢酸エチル、クロロホルム、塩化メチレン、
トルエンなど）で抽出すれば、光学分割剤である光学活
性プロピオン酸化合物を回収することができる。The aqueous layer after extraction is treated with a suitable mineral acid (eg, hydrochloric acid, sulfuric acid, etc.), and then treated with a suitable solvent (eg,
Ether, ethyl acetate, chloroform, methylene chloride,
Extraction with toluene or the like) allows recovery of an optically active propionic acid compound as an optical resolving agent.
【００３３】なお、原料である式（II）のラセミ型ピペ
リジン誘導体は、特公平５−３３９５３号公報にその製
法と共に記載されている。光学分割剤である式（III)の
光学活性プロピオン酸化合物は、例えば特公昭６３−１
３９９４号公報記載の方法に準じて製造することができ
る。The raw material of the racemic piperidine derivative of the formula (II) is described in Japanese Patent Publication No. 5-33953 together with its production method. The optically active propionic acid compound of the formula (III), which is an optical resolving agent, is described, for example, in JP-B-63-1.
It can be produced according to the method described in Japanese Patent No. 3994.
【００３４】本発明の方法のより具体的な例を下記に示
す。A more specific example of the method of the present invention is shown below.
【００３５】[0035]
【化１３】 Embedded image
【００３６】ラセミ型４−〔（４−クロロフェニル）
（２−ピリジル）メトキシ〕ピペリジンに、（２Ｒ，３
Ｒ）−２−ヒドロキシ−３−（４−メトキシフェニル）
−３−（２−ニトロ−５−クロロフェニルチオ）プロピ
オン酸（光学分割剤）を作用させ、難溶性ジアステレオ
マー塩として析出してくる（Ｓ）−４−〔（４−クロロ
フェニル）（２−ピリジル）メトキシ〕ピペリジンと
（２Ｒ，３Ｒ）−２−ヒドロキシ−３−（４−メトキシ
フェニル）−３−（２−ニトロ−５−クロロフェニルチ
オ）プロピオン酸との塩を分離・採取し、次いで該塩を
分解して、（Ｓ）−４−〔（４−クロロフェニル）（２
−ピリジル）メトキシ〕ピペリジンを得る。Racemic 4-[(4-chlorophenyl)
(2-pyridyl) methoxy] piperidine has (2R, 3
R) -2-Hydroxy-3- (4-methoxyphenyl)
-3- (2-Nitro-5-chlorophenylthio) propionic acid (optically resolving agent) is allowed to act to precipitate (S) -4-[(4-chlorophenyl) (2- A salt between (pyridyl) methoxy] piperidine and (2R, 3R) -2-hydroxy-3- (4-methoxyphenyl) -3- (2-nitro-5-chlorophenylthio) propionic acid was separated and collected, and then the salt was collected. The salt is decomposed to give (S) -4-[(4-chlorophenyl) (2
-Pyridyl) methoxy] piperidine.
【００３７】本明細書中、難溶性ジアステレオマー塩と
は、１対のジアステレオマー塩のうち溶媒に対する溶解
度がより低いジアステレオマー塩を意味する。In the present specification, a poorly soluble diastereomer salt means a diastereomer salt having a lower solubility in a solvent among a pair of diastereomer salts.
【００３８】以下実施例により具体的に説明するが、本
発明はこれによって限定されるものではない。Hereinafter, the present invention will be described in detail with reference to Examples, but the present invention is not limited thereto.
【００３９】本明細書の実施例においては、（Ｒ）型と
（Ｓ）型のピペリジン誘導体の量比（鏡像体過剰率：％
ｅ．ｅ．）は、次の条件での高速液体クロマトグラフィ
ーにより分析した。 カラム：ＵＬＴＯＲＯＮ−ＥＳ−ＯＵＭ（４．６Φ×１
５０mm）（信和化工（株）社製） 移動相：２０mMＫＨ2 ＰＯ4 水溶液（pH４．６）／エタ
ノール（１００：１０） 流量：１．０ml／分 検出波長：ＵＶ−２２０nmIn the examples of the present specification, the quantitative ratio of the (R) type and (S) type piperidine derivatives (enantiomeric excess:%
e. e. ) Was analyzed by high performance liquid chromatography under the following conditions. Column: ULTORON-ES-OUM (4.6Φ × 1
50 mm) (Shinwa Kako Co., Ltd.) Mobile phase: 20 mM KH 2 PO 4 aqueous solution (pH 4.6) / ethanol (100: 10) Flow rate: 1.0 ml / min Detection wavelength: UV-220 nm
【００４０】[0040]
【実施例】実施例１ （１）ラセミ型４−〔（４−クロロフェニル）（２−ピ
リジル）メトキシ〕ピペリジン１．０ｇと（２Ｒ，３
Ｒ）−２−ヒドロキシ−３−（４−メトキシフェニル）
−３−（２−ニトロ−５−クロロフェニルチオ）プロピ
オン酸１．２７ｇを、エタノール３０mlと水７mlの混液
に加熱溶解し、徐冷後２５℃で２時間撹拌した。析出晶
をろ過により集め、エタノールで洗浄後、５０℃で減圧
乾燥して、（Ｓ）−４−〔（４−クロロフェニル）（２
−ピリジル）メトキシ〕ピペリジンと（２Ｒ，３Ｒ）−
２−ヒドロキシ−３−（４−メトキシフェニル）−３−
（２−ニトロ−５−クロロフェニルチオ）プロピオン酸
との塩の粗結晶０．９７ｇを得た。 〔α〕D 25 −１１．７°（ｃ＝１，ジメチルホルムアミ
ド） ９４．１％ｅ．ｅ．EXAMPLE 1 (1) 1.0 g of racemic 4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidine and (2R, 3
R) -2-Hydroxy-3- (4-methoxyphenyl)
1.27 g of -3- (2-nitro-5-chlorophenylthio) propionic acid was dissolved by heating in a mixture of 30 ml of ethanol and 7 ml of water, followed by slow cooling and stirring at 25 ° C for 2 hours. The precipitated crystals were collected by filtration, washed with ethanol, and dried at 50 ° C. under reduced pressure to give (S) -4-[(4-chlorophenyl) (2
-Pyridyl) methoxy] piperidine and (2R, 3R)-
2-hydroxy-3- (4-methoxyphenyl) -3-
0.97 g of crude crystals of a salt with (2-nitro-5-chlorophenylthio) propionic acid were obtained. [Α] D 25 -11.7 ° (c = 1, dimethylformamide) 94.1% e. e.
【００４１】（２）この粗結晶０．８０ｇをエタノール
２０mlと水４mlの混液中で再結晶して、結晶０．７１ｇ
を得た。 〔α〕D 25 −１０．９°（ｃ＝１，ジメチルホルムアミ
ド） １００％ｅ．ｅ．(2) 0.80 g of the crude crystals were recrystallized in a mixture of 20 ml of ethanol and 4 ml of water to obtain 0.71 g of crystals.
I got [Α] D 25 -10.9 ° (c = 1, dimethylformamide) 100% e. e.
【００４２】（３）この再結晶品０．３５ｇを水３mlと
ジメチルホルムアミド０．５mlの混液に溶解し、１M 水
酸化ナトリウム水溶液０．７６mlを加えて分解し、３回
エーテルで抽出した。エーテル層を飽和食塩水で洗浄
後、硫酸ナトリウムで乾燥し、エーテルを留去してオイ
ル状の目的物（Ｓ）−４−〔（４−クロロフェニル）
（２−ピリジル）メトキシ〕ピペリジン０．１４ｇを得
た。 〔α〕D 25 −２１．６°（ｃ＝０．９９，エタノール） １００％ｅ．ｅ．(3) 0.35 g of the recrystallized product was dissolved in a mixture of 3 ml of water and 0.5 ml of dimethylformamide, decomposed by adding 0.76 ml of a 1M aqueous sodium hydroxide solution, and extracted three times with ether. The ether layer was washed with a saturated saline solution, dried over sodium sulfate, and the ether was distilled off to remove the oily product (S) -4-[(4-chlorophenyl).
(2-Pyridyl) methoxy] piperidine was obtained in an amount of 0.14 g. [Α] D 25 -21.6 ° (c = 0.99, ethanol) 100% e. e.
【００４３】実施例２ ラセミ型４−〔（４−クロロフェニル）（２−ピリジ
ル）メトキシ〕ピペリジンと（２Ｒ，３Ｒ）−２−ヒド
ロキシ−３−（４−メトキシフェニル）−３−（２−ニ
トロフェニルチオ）プロピオン酸を実施例１−（１）、
（２）及び（３）と同様に処理して（Ｓ）−４−〔（４
−クロロフェニル）（２−ピリジル）メトキシ〕ピペリ
ジンを得た。Example 2 Racemic 4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidine and (2R, 3R) -2-hydroxy-3- (4-methoxyphenyl) -3- (2-nitro Phenylthio) propionic acid was prepared in Example 1- (1),
The same processing as (2) and (3) is performed and (S) -4-[(4
-Chlorophenyl) (2-pyridyl) methoxy] piperidine.
【００４４】実施例３ （１）ラセミ型４−〔（４−クロロフェニル）（２−ピ
リジル）メトキシ〕ピペリジン２．０ｇと（２Ｒ，３
Ｒ）−２−ヒドロキシ−３−（４−メトキシフェニル）
−３−（２−ニトロ−５−クロロフェニルチオ）プロピ
オン酸１．５２ｇをエタノール２５mlと水５mlの混液に
加熱溶解し、５０℃で少量の種晶を加えた後２５℃で２
時間撹拌した。析出晶をろ過により集め、エタノールで
洗浄後、５０℃で減圧乾燥して、（Ｓ）−４−〔（４−
クロロフェニル）（２−ピリジル）メトキシ〕ピペリジ
ンと（２Ｒ，３Ｒ）−２−ヒドロキシ−３−（４−メト
キシフェニル）−３−（２−ニトロ−５−クロロフェニ
ルチオ）プロピオン酸との塩の粗結晶１．９５ｇを得
た。 〔α〕D 26 −１１．６°（ｃ＝１，ジメチルホルムアミ
ド） ９４．０％ｅ．ｅ．EXAMPLE 3 (1) 2.0 g of racemic 4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidine and (2R, 3
R) -2-Hydroxy-3- (4-methoxyphenyl)
1.52 g of -3- (2-nitro-5-chlorophenylthio) propionic acid was dissolved by heating in a mixture of 25 ml of ethanol and 5 ml of water, and a small amount of seed crystals were added at 50 ° C.
Stirred for hours. The precipitated crystals were collected by filtration, washed with ethanol, dried at 50 ° C. under reduced pressure to give (S) -4-[(4-
Crude crystals of a salt of (chlorophenyl) (2-pyridyl) methoxy] piperidine with (2R, 3R) -2-hydroxy-3- (4-methoxyphenyl) -3- (2-nitro-5-chlorophenylthio) propionic acid 1.95 g were obtained. [Α] D 26 -11.6 ° (c = 1, dimethylformamide) 94.0% e. e.
【００４５】（２）この粗結晶１．７０ｇをエタノール
４２mlと水８．５mlの混液中で再結晶して、結晶１．５
３ｇを得た。 〔α〕D 25 −１１．０°（ｃ＝１，ジメチルホルムアミ
ド） １００％ｅ．ｅ．(2) 1.70 g of the crude crystals were recrystallized in a mixture of 42 ml of ethanol and 8.5 ml of water to give 1.5
3 g were obtained. [Α] D 25 -11.0 ° (c = 1, dimethylformamide) 100% e. e.
【００４６】（３）この再結晶品を実施例１−（３）と
同様に処理して、（Ｓ）−４−〔（４−クロロフェニ
ル）（２−ピリジル）メトキシ〕ピペリジンを得た。(3) The recrystallized product was treated in the same manner as in Example 1- (3) to obtain (S) -4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidine.
【００４７】実施例４ （１）ラセミ型４−〔（４−クロロフェニル）（２−ピ
リジン）メトキシ〕ピペリジン１．０ｇと（２Ｓ，３
Ｓ）−２−ヒドロキシ−３−（４−メトキシフェニル）
−３−（２−ニトロフェニルチオ）プロピオン酸１．１
５ｇをエタノール１０mlと水２mlの混液に加熱溶解し、
徐冷後２５℃で２時間撹拌した。析出晶をろ過により集
め、エタノールで洗浄後、５０℃で減圧乾燥して、
（Ｒ）−４−〔（４−クロロフェニル）（２−ピリジ
ル）メトキシ〕ピペリジンと（２Ｓ，３Ｓ）−２−ヒド
ロキシ−３−（４−メトキシフェニル）−３−（２−ニ
トロフェニルチオ）プロピオン酸との塩の粗結晶０．８
４ｇを得た。 〔α〕D 25 −４０．６°（ｃ＝１，ジメチルホルムアミ
ド） ８９．８％ｅ．ｅ．Example 4 (1) 1.0 g of racemic 4-[(4-chlorophenyl) (2-pyridine) methoxy] piperidine and (2S, 3
S) -2-Hydroxy-3- (4-methoxyphenyl)
-3- (2-nitrophenylthio) propionic acid 1.1
5 g is dissolved by heating in a mixture of 10 ml of ethanol and 2 ml of water,
After slow cooling, the mixture was stirred at 25 ° C for 2 hours. The precipitated crystals were collected by filtration, washed with ethanol, dried at 50 ° C. under reduced pressure,
(R) -4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidine and (2S, 3S) -2-hydroxy-3- (4-methoxyphenyl) -3- (2-nitrophenylthio) propion Crude crystals of salt with acid 0.8
4 g were obtained. [Α] D 25 -40.6 ° (c = 1, dimethylformamide) 89.8% e. e.
【００４８】（２）この粗結晶０．７０ｇをエタノール
８．４mlと水０．９mlの混液中で再結晶して、結晶０．
６１ｇを得た。 〔α〕D 25 −３８．９°（ｃ＝１，ジメチルホルムアミ
ド） １００％ｅ．ｅ．(2) 0.70 g of the crude crystals were recrystallized in a mixed solution of 8.4 ml of ethanol and 0.9 ml of water to obtain a crystal of 0.10 g.
61 g were obtained. [Α] D 25 -38.9 ° (c = 1, dimethylformamide) 100% e. e.
【００４９】（３）この再結晶品０．５０ｇを実施例１
−（３）と同様に処理して、（Ｒ）−４−〔（４−クロ
ロフェニル）（２−ピリジル）メトキシ〕ピペリジン
０．２１ｇを得た。 〔α〕D 25 ＋２１．３°（ｃ＝１，エタノール） １００％ｅ．ｅ．(3) In Example 1, 0.50 g of the recrystallized product was used.
The same treatment as in (3) was performed to obtain 0.21 g of (R) -4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidine. [Α] D 25 + 21.3 ° (c = 1, ethanol) 100% e. e.
───────────────────────────────────────────────────── フロントページの続き (56)参考文献 特開 平６−336480（ＪＰ，Ａ) 特開 平４−182467（ＪＰ，Ａ) 特開 平６−135958（ＪＰ，Ａ) 特開 平６−239742（ＪＰ，Ａ) (58)調査した分野(Int.Cl.7，ＤＢ名) C07D 401/12 C07B 57/00 350 C07M 7:00 ＣＡ（ＳＴＮ) ＲＥＧＩＳＴＲＹ（ＳＴＮ)────────────────────────────────────────────────── ─── Continuation of front page (56) References JP-A-6-336480 (JP, A) JP-A-4-182467 (JP, A) JP-A-6-135958 (JP, A) JP-A-6-135958 239742 (JP, A) (58) Fields investigated (Int. Cl. 7 , DB name) C07D 401/12 C07B 57/00 350 C07M 7:00 CA (STN) REGISTRY (STN)
Claims (6)
ピペリジン誘導体に、（２Ｒ，３Ｒ）−２−ヒドロキシ
−３−（４−メトキシフェニル）−３−（２−ニトロ−
５−クロロフェニルチオ）プロピオン酸、（２Ｒ，３
Ｒ）−２−ヒドロキシ−３−（４−メトキシフェニル）
−３−（２−ニトロフェニルチオ）プロピオン酸、（２
Ｓ，３Ｓ）−２−ヒドロキシ−３−（４−メトキシフェ
ニル）−３−（２−ニトロ−５−クロロフェニルチオ）
プロピオン酸及び（２Ｓ，３Ｓ）−２−ヒドロキシ−３
−（４−メトキシフェニル）−３−（２−ニトロフェニ
ルチオ）プロピオン酸から選ばれる光学活性プロピオン
酸化合物を作用させ、生成する２種のジアステレオマー
塩の溶解度差を利用して、一方のジアステレオマー塩を
分離・採取することを特徴とする、式（II）のラセミ型
ピペリジン誘導体の光学分割方法。1. A compound of the formula (II) (Wherein X represents a halogen atom), to a (2R, 3R) -2-hydroxy-3- (4-methoxyphenyl) -3- (2-nitro-
5-chlorophenylthio) propionic acid, (2R, 3
R) -2-Hydroxy-3- (4-methoxyphenyl)
-3- (2-nitrophenylthio) propionic acid, (2
(S, 3S) -2-hydroxy-3- (4-methoxyphenyl) -3- (2-nitro-5-chlorophenylthio)
Propionic acid and (2S, 3S) -2-hydroxy-3
An optically active propionic acid compound selected from-(4-methoxyphenyl) -3- (2-nitrophenylthio) propionic acid is allowed to act, and the difference in solubility between the two diastereomeric salts produced is used to make one of them. An optical resolution method for a racemic piperidine derivative of the formula (II), comprising separating and collecting diastereomeric salts.
ピペリジン誘導体に、（２Ｒ，３Ｒ）−２−ヒドロキシ
−３−（４−メトキシフェニル）−３−（２−ニトロ−
５−クロロフェニルチオ）プロピオン酸、（２Ｒ，３
Ｒ）−２−ヒドロキシ−３−（４−メトキシフェニル）
−３−（２−ニトロフェニルチオ）プロピオン酸、（２
Ｓ，３Ｓ）−２−ヒドロキシ−３−（４−メトキシフェ
ニル）−３−（２−ニトロ−５−クロロフェニルチオ）
プロピオン酸及び（２Ｓ，３Ｓ）−２−ヒドロキシ−３
−（４−メトキシフェニル）−３−（２−ニトロフェニ
ルチオ）プロピオン酸から選ばれる光学活性プロピオン
酸化合物を作用させ、生成する２種のジアステレオマー
塩の溶解度差を利用して、一方のジアステレオマー塩を
分離・採取し、次いで該塩を分解することを特徴とす
る、式（Ｖ） 【化５】 （式中、Ｘは前記と同一意味を有し、＊は不斉炭素原子
を表す）で示される光学活性ピペリジン誘導体の製法。2. A compound of the formula (II) (Wherein X represents a halogen atom), to a (2R, 3R) -2-hydroxy-3- (4-methoxyphenyl) -3- (2-nitro-
5-chlorophenylthio) propionic acid, (2R, 3
R) -2-Hydroxy-3- (4-methoxyphenyl)
-3- (2-nitrophenylthio) propionic acid, (2
(S, 3S) -2-hydroxy-3- (4-methoxyphenyl) -3- (2-nitro-5-chlorophenylthio)
Propionic acid and (2S, 3S) -2-hydroxy-3
An optically active propionic acid compound selected from-(4-methoxyphenyl) -3- (2-nitrophenylthio) propionic acid is allowed to act, and one of the two diastereomeric salts formed is used, utilizing the solubility difference between the two. A diastereomer salt is separated and collected, and then the salt is decomposed. (Wherein, X has the same meaning as described above, and * represents an asymmetric carbon atom).
（２−ピリジル）メトキシ〕ピペリジンに、（２Ｒ，３
Ｒ）−２−ヒドロキシ−３−（４−メトキシフェニル）
−３−（２−ニトロ−５−クロロフェニルチオ）プロピ
オン酸を作用させ、生成する２種のジアステレオマー塩
の溶解度差を利用して、一方のジアステレオマー塩を分
離・採取し、次いで該塩を分解することを特徴とする、
（Ｓ）−４−〔（４−クロロフェニル）（２−ピリジ
ル）メトキシ〕ピペリジンの製法。3. Racemic 4-[(4-chlorophenyl)
(2-pyridyl) methoxy] piperidine has (2R, 3
R) -2-Hydroxy-3- (4-methoxyphenyl)
-3- (2-Nitro-5-chlorophenylthio) propionic acid is allowed to act, and one diastereomer salt is separated and collected by utilizing the difference in solubility between the two diastereomeric salts formed. Characterized by decomposing salt,
A method for producing (S) -4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidine.
（２−ピリジル）メトキシ〕ピペリジンに、（２Ｒ，３
Ｒ）−２−ヒドロキシ−３−（４−メトキシフェニル）
−３−（２−ニトロフェニルチオ）プロピオン酸を作用
させ、生成する２種のジアステレオマー塩の溶解度差を
利用して、一方のジアステレオマー塩を分離・採取し、
次いで該塩を分解することを特徴とする、（Ｓ）−４−
〔（４−クロロフェニル）（２−ピリジル）メトキシ〕
ピペリジンの製法。4. Racemic 4-[(4-chlorophenyl)
(2-pyridyl) methoxy] piperidine has (2R, 3
R) -2-Hydroxy-3- (4-methoxyphenyl)
-3- (2-Nitrophenylthio) propionic acid is allowed to act, and one diastereomer salt is separated and collected by utilizing the difference in solubility between the two diastereomeric salts formed.
Then, the salt is decomposed, wherein (S) -4-
[(4-chlorophenyl) (2-pyridyl) methoxy]
Piperidine production method.
（２−ピリジル）メトキシ〕ピペリジンと（２Ｒ，３
Ｒ）−２−ヒドロキシ−３−（４−メトキシフェニル）
−３−（２−ニトロ−５−クロロフェニルチオ）プロピ
オン酸との塩。5. (S) -4-[(4-chlorophenyl)
(2-pyridyl) methoxy] piperidine and (2R, 3
R) -2-Hydroxy-3- (4-methoxyphenyl)
Salt with -3- (2-nitro-5-chlorophenylthio) propionic acid.
（２−ピリジル）メトキシ〕ピペリジンと（２Ｒ，３
Ｒ）−２−ヒドロキシ−３−（４−メトキシフェニル）
−３−（２−ニトロフェニルチオ）プロピオン酸との
塩。6. (S) -4-[(4-chlorophenyl)
(2-pyridyl) methoxy] piperidine and (2R, 3
R) -2-Hydroxy-3- (4-methoxyphenyl)
Salt with -3- (2-nitrophenylthio) propionic acid.
Priority Applications (20)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP34785196A JP3157117B2 (en) | 1996-12-26 | 1996-12-26 | Optical resolution method of piperidine derivative |
| TW086119702A TW486475B (en) | 1996-12-26 | 1997-12-24 | Acid addition salt of optically active piperidine compound and process for preparing the same |
| US09/331,792 US6307052B1 (en) | 1996-12-26 | 1997-12-25 | Acid-addition salts of optically active piperidine compound and process for producing the same |
| DK97949235T DK0949260T3 (en) | 1996-12-26 | 1997-12-25 | Acid addition salts of an optically active piperidine compound and process for its preparation |
| ES97949235T ES2173499T3 (en) | 1996-12-26 | 1997-12-25 | ADDITIONAL SALTS OF OPTICALLY ACTIVE PIPERIDINE COMPOUND ACIDS AND PROCEDURE FOR PREPARATION. |
| IDW990748A ID21985A (en) | 1996-12-26 | 1997-12-25 | ADDITIONAL SALT OF PYRIDINE COMPOUND ACIDS ARE OPTICAL AND THE PROCESS OF MAKING IT |
| KR10-1999-7005802A KR100515227B1 (en) | 1996-12-26 | 1997-12-25 | Acid-Addition Salts of Optically Active Piperidine Compound and Process for Producing the Same |
| PCT/JP1997/004826 WO1998029409A1 (en) | 1996-12-26 | 1997-12-25 | Acid-addition salts of optically active piperidine compound and process for producing the same |
| AT97949235T ATE217872T1 (en) | 1996-12-26 | 1997-12-25 | ACID ADDITION SALTS OF AN OPTICALLY ACTIVE PIPERIDINE COMPOUND AND METHOD FOR THE PRODUCTION THEREOF |
| CA002275987A CA2275987C (en) | 1996-12-26 | 1997-12-25 | Acid addition salt of optically active piperidine compound and process for preparing the same |
| CN97181039A CN1098262C (en) | 1996-12-26 | 1997-12-25 | Acid-addition salts of optically active piperidine compound and process for producing the same |
| PT97949235T PT949260E (en) | 1996-12-26 | 1997-12-25 | OPTICAL ACTIVE PIPERIDINE COMPOUND ACID ADDITION SALT AND PROCESS FOR THE PREPARATION OF THE SAME |
| AU78906/98A AU7890698A (en) | 1996-12-26 | 1997-12-25 | Acid-addition salts of optically active piperidine compounds and process for producing the same |
| DE69712784T DE69712784T2 (en) | 1996-12-26 | 1997-12-25 | ACID ADDITION SALTS OF AN OPTICALLY ACTIVE PIPERIDINE COMPOUND AND METHOD FOR THE PRODUCTION THEREOF |
| EP97949235A EP0949260B1 (en) | 1996-12-26 | 1997-12-25 | Acid-addition salts of optically active piperidine compound and process for producing the same |
| MYPI97006328A MY118016A (en) | 1996-12-26 | 1997-12-26 | Acid addition salt of optically active piperidine compound and process for preparing the same |
| HK00101619A HK1022477A1 (en) | 1996-12-26 | 2000-03-16 | Acid-addition salts of optically active piperidine compound and process for producing the same |
| US09/949,809 US6780877B2 (en) | 1996-12-26 | 2001-09-12 | Acid addition salt of optically active piperidine compound and process for preparing the same |
| CNB021271631A CN1231478C (en) | 1996-12-26 | 2002-07-30 | Acid-addition salt of hexahydropyridine compound having optical activity, and its prepn. process |
| US10/771,361 US7282589B2 (en) | 1996-12-26 | 2004-02-05 | Acid addition salt of optically active piperidine compound and process for preparing the same |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP34785196A JP3157117B2 (en) | 1996-12-26 | 1996-12-26 | Optical resolution method of piperidine derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JP2000159762A JP2000159762A (en) | 2000-06-13 |
| JP3157117B2 true JP3157117B2 (en) | 2001-04-16 |
Family
ID=18393037
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP34785196A Expired - Lifetime JP3157117B2 (en) | 1996-12-26 | 1996-12-26 | Optical resolution method of piperidine derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP3157117B2 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP5641802B2 (en) * | 2010-07-26 | 2014-12-17 | 株式会社トクヤマ | Process for producing diastereomeric salt of (S) -4-[(4-chlorophenyl) (2-pyridyl) methoxy] piperidine |
-
1996
- 1996-12-26 JP JP34785196A patent/JP3157117B2/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| JP2000159762A (en) | 2000-06-13 |
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